The aim of this proposal is to examine the various aspects of idiotype-anti-idiotye interactions in regulation of the immune response to the surface antigens of hepatitis B virus (HBsAg) and woodchuck hepatitis virus (WHsAg). The pathogenesis of acute and chronic hepatitis B in man is poorly understood but numerous studies suggest that abnormalities of immunoregulation are involved. In this project the principles of Jerne's idiotypic network hypothesis, for which there is now considerable experimental support, and two recently described animal model systems, will be used to study and to attempt to manipulate the humoral immune responses to HBsAg and WHsAg. Anti-idiotypic antibodies (anti-Id) against the idiotypes of monoclonal anti-HBs and anti-WHs will be prepared as antisera in rabbits and as monoclonal anti-Id by hybridoma technology. Congenic and non-congenic inbred mouse strains showing H2 restriction for the humoral immune response to HBsAg will serve as one model for anti-Id manipulation. The relative expression of different idiotypes in high and low responder strains during the course of the anti-HBs and anti-WHs responses will be monitored in radioimmunoassays (RIA) utilizing the anti-Id reagents. Specific anti-Id will then be administered in vivo to mice in attempts to induce idiotype-positive antibody molecules in the absence of antigen exposure. In other experiments in vivo treatment with anti-Id will be followed by antigen challenge and the extent of enhancement of suppression of the total and idiotype-specific anti-HBs or anti-WHs response will be measured by RIA. Attention will also focus on genetic differences in the response to anti-Id and on the potential for extension of anti-Id manipulation to the woodchuck model of viral hepatitis. In addition, an attempt will be made to identify the anti-idiotypic reagents which share antigenic determinants with HBsAg and/or WHsAg. Such reagents will then be tested as immunogens in the woodchuck model for their ability to induce protective antibodies against woodchuck hepatitis virus and as possible anti-viral receptor antibodies in other systems.